title: AZA-deoxycytidine stimulates proopiomelanocortin gene expression and ACTH secretion in human pituitary ACTH-secreting tumors.
abstract: OBJECTIVE
  It is well known that methylation plays an important role in regulating tissue expression of proopiomelanocortin (POMC) and recent studies have shown that demethylation can occur also in vitro in neuroendocrine tumors. Aim of the present study was to evaluate whether inhibition of methylation modulates POMC expression and ACTH secretion by human corticotrope tumors.
  
  
  METHODS
  Twenty two ACTH-secreting pituitary tumors were incubated with 5-AZA-2'-deoxycytidine (AZA), an inhibitor of DNA-methyltransferases, with or without 10 nM corticotropin-releasing hormone (CRH). Both dose response (100 nM-10 μM AZA) and time course (4-96 h) experiments were carried out for measurement of ACTH secretion and POMC gene expression.
  
  
  RESULTS
  Incubation with AZA increased constitutive POMC expression and ACTH secretion by human corticotrope adenomas. The effect appeared most notable at 24 and 48 h with 1 μM AZA. Incubation with AZA did not exert an additional stimulatory effect on CRH-stimulated POMC and ACTH.
  
  
  CONCLUSIONS
  The present study shows that AZA increases POMC gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. This can be taken to indicate that mechanisms set into motion by AZA play a role in the regulation of ACTH secretion/POMC expression in tumoral corticotropes and paves the way to further studies in Cushing's disease.
authors.affiliation: Neuroendocrinology Research Laboratory, Istituto Auxologico Italiano IRCCS, Piazzale Brescia 20, Milan, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Cassarino
authors.forename: Antonella
authors.initials: A
authors.lastname: Sesta
authors.forename: Luca
authors.initials: L
authors.lastname: Pagliardini
authors.forename: Marco
authors.initials: M
authors.lastname: Losa
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lasio
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavagnini
authors.forename: Francesca
authors.initials: F
authors.lastname: Pecori Giraldi
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000188:drug therapy* / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics*
chemical_list: D011333:Pro-Opiomelanocortin; D000077209:Decitabine; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D001374:Azacitidine